{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:49:00Z","timestamp":1791978540694,"version":"4.4.0"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T00:00:00Z","timestamp":1705708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Office of Hungary","award":["FK131916"],"award-info":[{"award-number":["FK131916"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["K146130"],"award-info":[{"award-number":["K146130"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["EFOP-3.6.1-16-2016-00008"],"award-info":[{"award-number":["EFOP-3.6.1-16-2016-00008"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["GINOP-2.3.2-15-2016-00039"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00039"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["GINOP-2.3.4-15-2020-00010"],"award-info":[{"award-number":["GINOP-2.3.4-15-2020-00010"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["GINOP-2.3.1-20-2020-00001"],"award-info":[{"award-number":["GINOP-2.3.1-20-2020-00001"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["TKP-2021-EGA-13"],"award-info":[{"award-number":["TKP-2021-EGA-13"]}]},{"name":"National Research, Development and Innovation Office of Hungary","award":["TRR152 P12"],"award-info":[{"award-number":["TRR152 P12"]}]},{"name":"ELIXIR Hungary","award":["FK131916"],"award-info":[{"award-number":["FK131916"]}]},{"name":"ELIXIR Hungary","award":["K146130"],"award-info":[{"award-number":["K146130"]}]},{"name":"ELIXIR Hungary","award":["EFOP-3.6.1-16-2016-00008"],"award-info":[{"award-number":["EFOP-3.6.1-16-2016-00008"]}]},{"name":"ELIXIR Hungary","award":["GINOP-2.3.2-15-2016-00039"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00039"]}]},{"name":"ELIXIR Hungary","award":["GINOP-2.3.4-15-2020-00010"],"award-info":[{"award-number":["GINOP-2.3.4-15-2020-00010"]}]},{"name":"ELIXIR Hungary","award":["GINOP-2.3.1-20-2020-00001"],"award-info":[{"award-number":["GINOP-2.3.1-20-2020-00001"]}]},{"name":"ELIXIR Hungary","award":["TKP-2021-EGA-13"],"award-info":[{"award-number":["TKP-2021-EGA-13"]}]},{"name":"ELIXIR Hungary","award":["TRR152 P12"],"award-info":[{"award-number":["TRR152 P12"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["FK131916"],"award-info":[{"award-number":["FK131916"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["K146130"],"award-info":[{"award-number":["K146130"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["EFOP-3.6.1-16-2016-00008"],"award-info":[{"award-number":["EFOP-3.6.1-16-2016-00008"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["GINOP-2.3.2-15-2016-00039"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00039"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["GINOP-2.3.4-15-2020-00010"],"award-info":[{"award-number":["GINOP-2.3.4-15-2020-00010"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["GINOP-2.3.1-20-2020-00001"],"award-info":[{"award-number":["GINOP-2.3.1-20-2020-00001"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["TKP-2021-EGA-13"],"award-info":[{"award-number":["TKP-2021-EGA-13"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","doi-asserted-by":"publisher","award":["TRR152 P12"],"award-info":[{"award-number":["TRR152 P12"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Albinism is characterized by a variable degree of hypopigmentation affecting the skin and the hair, and causing ophthalmologic abnormalities. Its oculocutaneous, ocular and syndromic forms follow an autosomal or X-linked recessive mode of inheritance, and 22 disease-causing genes are implicated in their development. Our aim was to clarify the genetic background of a Hungarian albinism cohort. Using a 22-gene albinism panel, the genetic background of 11 of the 17 Hungarian patients was elucidated. In patients with unidentified genetic backgrounds (n = 6), whole exome sequencing was performed. Our investigations revealed a novel, previously unreported rare variant (N687S) of the two-pore channel two gene (TPCN2). The N687S variant of the encoded TPC2 protein is carried by a 15-year-old Hungarian male albinism patient and his clinically unaffected mother. Our segregational analysis and in vitro functional experiments suggest that the detected novel rare TPCN2 variant alone is not a disease-causing variant in albinism. Deep genetic analyses of the family revealed that the patient also carries a phenotype-modifying R305W variant of the OCA2 protein, and he is the only family member harboring this genotype. Our results raise the possibility that this digenic combination might contribute to the observed differences between the patient and the mother, and found the genetic background of the disease in his case.<\/jats:p>","DOI":"10.3390\/ijms25021271","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T03:50:22Z","timestamp":1705895422000},"page":"1271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8576-7953","authenticated-orcid":false,"given":"Nikoletta","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Functional Clinical Genetic Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3662-0837","authenticated-orcid":false,"given":"Margit","family":"Pal","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Functional Clinical Genetic Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozsef","family":"Kun","sequence":"additional","affiliation":[{"name":"Hungarian Centre for Genomics and Bioinformatics, Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-7005","authenticated-orcid":false,"given":"Bence","family":"Galik","sequence":"additional","affiliation":[{"name":"Hungarian Centre for Genomics and Bioinformatics, Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4043-3428","authenticated-orcid":false,"given":"Peter","family":"Urban","sequence":"additional","affiliation":[{"name":"Hungarian Centre for Genomics and Bioinformatics, Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-096X","authenticated-orcid":false,"given":"Marta","family":"Medvecz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, 1095 Budapest, Hungary"},{"name":"ERN-Skin Reference Centre, Semmelweis University, 1095 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Fabos","sequence":"additional","affiliation":[{"name":"Mor Kaposi Teaching Hospital of Somogy County, 7400 Kaposvar, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Neller","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliasgari","family":"Abdolreza","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0270-5309","authenticated-orcid":false,"given":"Judit","family":"Danis","sequence":"additional","affiliation":[{"name":"HUN-REN-SZTE Dermatological Research Group, 6720 Szeged, Hungary"},{"name":"Department of Immunology, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6994-8401","authenticated-orcid":false,"given":"Stefanie","family":"Fenske","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Biel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Gyenesei","sequence":"additional","affiliation":[{"name":"Hungarian Centre for Genomics and Bioinformatics, Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Adam","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Functional Clinical Genetic Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Szell","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary"},{"name":"HUN-REN-SZTE Functional Clinical Genetic Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101091","DOI":"10.1016\/j.preteyeres.2022.101091","article-title":"The retinal pigmentation pathway in human albinism: Not so black and white","volume":"91","author":"Bakker","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00439-022-02489-y","article-title":"PMEL is mutated in oculocutaneous albinism","volume":"142","author":"AlAbdi","year":"2023","journal-title":"Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev-genom-083118-015230","article-title":"The Genetics of Human Skin and Hair Pigmentation","volume":"20","author":"Pavan","year":"2019","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.lpm.2017.05.020","article-title":"Clinique et g\u00e9n\u00e9tique de l\u2019albinisme [Clinical and genetic aspects of albinism]","volume":"46","author":"Arveiler","year":"2017","journal-title":"Presse Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/pcmr.12688","article-title":"Molecular characterization of a series of 990 index patients with albinism","volume":"31","author":"Lasseaux","year":"2018","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.jid.2019.12.010","article-title":"Albinism: An Underdiagnosed Condition","volume":"140","author":"Arveiler","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1038\/s41467-022-31392-3","article-title":"The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism","volume":"13","author":"Michaud","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/pcmr.12982","article-title":"Genetics of non-syndromic and syndromic oculocutaneous albinism in human and mouse","volume":"34","author":"Hayashi","year":"2021","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/humu.22315","article-title":"orgDNA Variations in Oculocutaneous Albinism: An UpdatedMutation List and Current Outstanding Issues in MolecularDiagnostics","volume":"34","author":"Simeonov","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Maroilley, T., and Tarailo-Graovac, M. (2019). Uncovering Missing Heritability in Rare Diseases. Genes, 10.","DOI":"10.3390\/genes10040275"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2147\/TACG.S288274","article-title":"Genetic Testing in CYLD Cutaneous Syndrome: An Update","volume":"14","author":"Nagy","year":"2021","journal-title":"Appl. Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41467-023-35786-9","article-title":"A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation","volume":"14","author":"Wang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102543","DOI":"10.1016\/j.ceca.2022.102543","article-title":"Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2. Five things to know","volume":"103","author":"Patel","year":"2022","journal-title":"Cell Calcium"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e45222","DOI":"10.7554\/eLife.45222","article-title":"Structural mechanisms of phospholipid activation of the human TPC2 channel","volume":"8","author":"She","year":"2019","journal-title":"eLife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.cell.2012.08.036","article-title":"TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes","volume":"151","author":"Wang","year":"2012","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"B\u00f6ck, J., Krogsaeter, E., Passon, M., Chao, Y.-K., Sharma, S., Grallert, H., Peters, A., and Grimm, C. (2021). Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect. PLoS Genet., 17.","DOI":"10.1371\/journal.pgen.1009236"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E8595","DOI":"10.1073\/pnas.1705739114","article-title":"TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms","volume":"114","author":"Chao","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41525-021-00275-9","article-title":"Evidence that the Ser192Tyr\/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B)","volume":"7","author":"Lin","year":"2022","journal-title":"npj Genom. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5622","DOI":"10.1073\/pnas.1600108113","article-title":"TPC2 controls pigmentation by regulating melanosome pH and size","volume":"113","author":"Ambrosio","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e04543","DOI":"10.7554\/eLife.04543","article-title":"An intracellular anion channel critical for pigmentation","volume":"3","author":"Bellono","year":"2014","journal-title":"eLife"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/cge.13150","article-title":"Digenic inheritance and genetic modifiers","volume":"93","author":"Deltas","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1111\/jdv.17275","article-title":"Management of albinism: French guidelines for diagnosis and care","volume":"35","author":"Dufresne","year":"2021","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1038\/s41431-022-01191-x","article-title":"Assessing the digenic model in rare disorders using population sequencing data","volume":"30","author":"Lao","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1016\/j.csbj.2022.07.011","article-title":"An accurate prediction model of digenic interaction for estimatingpathogenic gene pairs of human disease","volume":"20","author":"Yuan","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/1271\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:46:16Z","timestamp":1760103976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/1271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,20]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25021271"],"URL":"https:\/\/doi.org\/10.3390\/ijms25021271","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,20]]}}}